Alzheimer's disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid β peptide (Aβ). Aβ is a 39-43 amino acid produced in the brain by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme (“beta secretase” or “BACE”) and gamma-secretase. The processing leads to accumulation of Aβ in the brain.
Cholinergic neurotransmission involves the binding of acetylcholine either to the nicotinic acetylcholine receptor (nAChR) or to the muscarinic acetylcholine receptor (mAChR). It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer's Disease. Consequently, pharmacotherapeutic targets which increase the activation of muscarinic receptors to counteract cholinergic hypofunction have been explored. Muscarinic receptors are prevalent throughout the body. Five distinct muscarinic receptors (M1-M5) have been identified in mammals. In the central nervous system, muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions. The muscarinic M1 receptor, which is prevalent in the cerebral cortex, hippocampus and striatum, has been found to have a major role in cognitive processing and is believed to have a role in the pathophysiology of Alzheimer's Disease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001, 22:8, 409-414. Additionally, M1 agonists also have the potential to treat the underlying disease mechanism of Alzheimer's Disease. The cholinergic hypothesis of Alzheimer's Disease is linked to both β-amyloid and hyperphosphorylated tau protein. Formation of β-amyloid may impair the coupling of the muscarinic receptor with G-proteins. Stimulation of the M1 muscarinic receptor has been shown to increase formation of the neuroprotective αAPPs fragment, thereby preventing the formation of the Aβ peptide. Thus, M1 agonists may alter APP processing and enhance αAPPs secretion. See Fisher, Jpn J Pharmacol, 2000, 84:101-112.
Among the compounds thought to be useful for treating Alzheimer's disease are M1 receptor positive allosteric modulators of the kind illustrated in WO2010/059773, published May 27, 2010 and US2011-0224198, published Sep. 15, 2011, both of which are incorporated herein by reference in their entirety. Intermediates of the compounds disclosed herein are discussed in Tetrahedron Letters 44 (2003) 319-322. See also Journal of Biological Chemistry, vol. 289(48), 2014, pp 33701-33711. The present invention is directed to a novel process for synthesizing M1 receptor positive allosteric modulators which are substituted aryl methyl benzoquinazolinone compounds of the kind disclosed in WO2010/059773. The present invention is also directed to a novel process for synthesizing substituted aryl methyl benzoquinazolinone compounds under milder and more robust and predictable conditions. The compounds synthesized by the processes of the invention are useful for treating Alzheimer's disease and other diseases mediated by the muscarinic M1 receptor. Processes for making intermediates of the compounds disclosed herein can be found in WO2010/059773. See also Yu-Liang Yang et al., Tetrahedron Ltrs 44 (2003) 319-322.